ALCOHOL & PERIPHERAL-TYPE BENZODIAZEPINE RECEPTORS

长期的目标是确定分子的变化， 调节乙醇作用的大脑， 预防和治疗酒精中毒的信息。 的 研究目的是提供基本信息 外周型苯二氮卓受体（PBR）的作用 研究乙醇对脑PBR的急性影响 功能，检查慢性乙醇暴露引起的变化， 小鼠脑PBR，并确定这些变化的重要性 对酒精的依赖。 具体目标是：（1） 研究脑PBR的功能，并确定乙醇是否 （2）确定是否存在行为上的差异; 乙醇与作用于PBR的药物之间的相互作用; 3） 描述慢性乙醇暴露引起的变化， C57BL/6J小鼠脑PBR，通过确定该效应是否 对脑区域或亚细胞部分具有选择性; 4） 描述乙醇诱导的脑变化的时间过程 C57 BL/6J小鼠在乙醇获得和损失期间的PBR 5）确定慢性药物依赖引起的变化是否 酒精暴露在大脑PBR系统是一种普遍的反应， 跨越小鼠性别和品系延伸;以及6）研究 脑PBR系统在调节乙醇中的重要性 C57 BL/6J小鼠中的依赖性，通过确定 一个假定的内源性legnad的大脑水平， 确定PBR选择性激动剂或拮抗剂改变 身体依赖的获得和表达。 实现 雄性大鼠、雄性和雌性C57 BL/6J以及雄性WSP 将使用WSR和DBA/2小鼠。 乙醇或等卡路里 葡萄糖将通过流质饮食长期给药。 乙醇， 盐水、赋形剂和药物将通过i.p. 注射或体外添加。 乙醇的急性影响将是 使用自发活动、睡眠时间、唤醒血液定量 乙醇浓度（BEC）和直肠温度（RT）。 将使用中毒等级、RT、 BEC、PBR结合特性和一种假定的 PBR内源性配体。 乙醇依赖的发展 将通过戒断反应的存在来衡量。 的 退出的严重程度将使用退出来确定 共济失调、震颤、自发性惊厥和处理指数- 诱发抽搐 这些研究将导致更好的 了解大脑苯二氮卓系统在 酒精滥用和酒精中毒。

The long-term objective is to identify molecular changes in the brain that mediate the effects of ethanol and to apply this information in the prevention and treatment of alcoholism. The purpose of the proposed research is to provide basic information on the role of the peripheral-type benzodiazepine receptors (PBR) in the brain, study the acute effect of ethanol on brain PBR function, examine changes induced by chronic ethanol exposure in mouse brain PBR and determine the importance of these changes in mediating ethanol dependence. The specific aims are to 1) Study the function of brain PBR and determine whether ethanol alters their function; 2) Determine whether there are behavioral interactions between ethanol and drugs acting on the PBR; 3) Characterize the changes induced by chronic ethanol exposure on C57BL/6J mouse brain PBR by determining if the effect is selective for brain regions or sub-cellular fraction; 4) Characterize the time course for ethanol-induced changes in brain PBR in C57BL/6J mice during acquisition and loss of ethanol dependence; 5) Determine whether the changes induced by chronic ethanol exposure in the brain PBR system are a general response extending across mouse gender and strains; and 6) Investigate the importance of the brain PBR system in mediating ethanol dependence in C57BL/6J mice by determining if changes occurr in the brain level of a putative endogenous legnad and by determining PBR-selective agonists or antagonists alter the acquisition and expression of physical dependence. To achieve these goals, male rats, male and female C57BL/6J and male WSP WSR and DBA/2 mice will be used. Ethanol or equicaloric dextrose will be chronically administered by liquid diet. Ethanol, saline, vehicles and drugs will be acutely administered by i.p. injection or added in vitro. Acute effects of ethanol will be quantitated using locomotor activity, sleep-time, wake-up blood ethanol concentration (BEC) and rectal temperature (RT). Chronic effects will be quantitated using intoxication ratings, RT, BEC, PBR binding properties, and the brain levels of a putative PBR endogenous ligand. The development of ethanol dependence will be measured by the presence of a withdrawal reaction. The severity of withdrawal will be determined using a withdrawal index of ataxia, tremor, spontaneous convulsions and handling- induced convulsions. These studies will lead to a better understanding of the role of brain benzodiazepine systems in alcohol abuse and alcoholism.